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biRocheEmisDtry bRloUcMk 2 Tulane School of Headaches Part 3
Biochemistry Block 2
102
Biochemistry
Post-Graduate
09/23/2012

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Term
Perlecan
Definition
Glycoprotein that contains N-linked, O-linked, and GAG polysaccharides / can bind to and cross link many ECM components / Important in basal lamina / abnormalities can cause dwarfism
Term
Proteoglycans
Definition
Glycoproteins that contain GAG polysaccharides
Term
Laminin
Definition
Multi-adhesion protein commonly found in basement membranes / Can bind collagen, sulfated lipids, axons, and dendrites
Term
Fibronectin
Definition
Most abundant multi-adhesion protein in the ECM
Term
GAG polysaccharides
Definition
Unbranched polysaccharides usually (uronic acid and an amino sugar) / They contain negative charge from carboxylic acid and sulfate functional group... thus imbibe lots of water / Found in cartilage / Usually bound to a protein core
Term
Core proteins of proteoglycans
Definition
involved in mediating signals from the outside of the cell to the interior / GAG may extend extracellularly while the core proteins produce cytosolic signals when GAG binds to ligand ig Syndecan-4
Term
Osteoarthritis (OA)
Definition
Often a result of cartilage degeneration (more specifically the proteoglycan Aggrecan and type II collagen)
Term
Aggrecan
Definition
Location: Cartilage Function: Mechanical support, forms large aggregrates with hyaluronic acid (support), binds to TGF-Beta (stops ECM production)
Term
Decorin
Definition
Location: Widespread in ECM Function: Bings to type I collagen fibrils (limits size)
Term
Fibronectin
Definition
Two nearly identical polypeptide joined by two disulfide bonds/ Has various globular domains for ECMs or specific domains to bind / Cell surface receptors receptors binds domains have RGD which is recognized by fibronectin receptor
Term
Where and when is Laminin produced?
Definition
Epithelial and endothelial cells and is important for neuronal development / One of the first
Term
Loss of function laminin-1
Definition
Causes cell division to be arrested very early in development
Term
Major Protein Components of the Basal Lamina
Definition
Collagen: Type IV / Proteoglycan: Perlecan / Multi-adhesive matrix protein: Laminin / ENTACTIN: protein cross-linker
Term
Cadherins
Definition
Bind by homophilic (same to same) interactions / Present in desmosomes and mediate cell adhesion in development
Term
NCAM (Ig-superfamily)
Definition
Bind by homophilic (same to same) interactions / Similar to Ig structure / Important in neuronal development
Term
Integrins
Definition
Heterophilic interactions / Bind to multi-adhesion matrix proteins (fibronectin)
Term
Selectins
Definition
Heterophilic interactions / Carb binding proteins, binding glycoproteins of other cells
Term
What cellular function are selectins important for?
Definition
Extravasation of leukocytes, movement of WBC from capillaries to tissues
Term
Injured tissues, platelets, and endothelial cells all express what during an injury?
Definition
PAF: Platelet activating factor
Term
What does PAF do in a cell?
Definition
It causes endothelial cells to express P-selectins?
Term
What happens when WBC selectin binds to p-selectin on the endothelial cell?
Definition
PAF binds to the PAF receptor
Term
What happens after PAF binds to the PAF receptor?
Definition
Adhesion of the WBC and endothelial cell occurs via WBC integtin and an Intercellular Adhesion Molecule (ICAM)... then extravastion
Term
What does a reduction of leukocyte extravasation also reduce? In what disease would this be useful for and why?
Definition
Inflammation / Multiple Sclerosis / Stops chronic inflammation
Term
Natalizaumab
Definition
Drug that reduces inflammation by blocking extravasion by WBC
Term
What motifs do many integrins recognize?
Definition
Acidic AA's like RGD motifs (infibronectin)
Term
Integrin signaling
Definition
Cell surface integrins can have active and inactive states depend on the state of the cell
Term
Talin and Vinculin
Definition
proteins that mediate interactions with the cytoplasmic cytoskeleton
Term
Paxillin-Focal Adhesion Kinase (FAK)
Definition
Uses Ras-MAP Kinase pathway to initiate cell signalling via integrins / used in polymerization of Actin Stress Fibers
Term
What intracellular signaling pathway proteins can integrins activate? And what will it do?
Definition
ERK1/2, P13K pathway, Rac/Rho/Cdc42 G-proteins / cytoskeleton, cell proliferation, cell survival, cell migration, and gene transcription
Term
Epidermolysis Bullosa?
Definition
Problems with Keratin
Term
Complex carbohydrates
Definition
Hetero-oligosaccharides or hetero-polysaccharides that contain more than one species of monosaccharides. Complex carbohydrates are usually linked to proteins and lipids to form glycoproteins and glycolipids.
Term
Glycoconjugates
Definition
Glycoproteins and glycolipids / The 3 major classes of glycoconjugates found in higher animals are glycoproteins, proteoglycans and glycosphingolipids.
Term
Structural Representation of Glucose
Definition
What makes D vs L, alpha vs beta, what is more prevalent, yaddy yaddy
Term
What is the driving force for the cyclization of the open chain Fisher D-Glucose form to closed Hayworth D-Glucose form
Definition
Hemiacetal formation
Term
Biochemical Basis of Protein Glycation
Definition
The first step of protein glycation
is the formation of a Schiff base.
The aldehyde group of glucose
reacts with an amino group of a
protein to form a Schiff base, or
an aldimine. This step is reversible. Since glucose contains an OH group at carbon 2, next to the Schiff base, the
Schiff base can undergo an Amadori rearrangement to form a stable ketoamine. These two steps are the most important steps for protein glycation.
Term
Hemoglobin HbA1C
Definition
HbA1C is formed by glycation of the N-terminal valine of the two β-chains in HbA (Figure 4). The two Nterminal valine residues of the two β-chains can react with two residues of the open chain form of glucose to form two Schiff bases or pre-HbA1C. The two Schiff bases undergo Amadori
rearrangement to form two stable ketoamines or HbA1C.
Term
Change from Glucose: Mannose
Definition
Mannose is the C-2 epimer of glucose .
Term
Change from Glucose: Galactose
Definition
Galactose is a C-4 epimer of D-glucose.
Term
Change from Glucose: D-Nacetylglucosamine
(GlcNAc)
Definition
Derived from D-glucose by modifying
the C-2 hydroxyl group into an Nacetyl
group.
Term
Change from Glucose: D-glucuronic acid
Definition
Converting the CH2OH at carbon 6 of D-glucose with a COOH group
Term
Change from D-Glucuronic acid: L-Iduronic acid
Definition
Epimerization of carbon 5 of D-glucuronic acid converts this sugar to L-iduronic acid
Term
Change from D-Nacetylglucosamine
(GlcNAc): N-Acetylgalactosamine
Definition
C-4-epimer of D-N-acetylglucosamine
Term
What is required for a glycosidic linkage?
Definition
nucleotide sugar donor, a sugar
acceptor, and a glycosyltransferase
Term
What are the major nucleotide sugar donors in glycosidic linkages?
Definition
UDP-sugar donors, GDP sugar donors and CMP-sugar donors. UDP
sugar donors include UDP-Gal, UDP-Glc,
UDP-GlcA, UDP-GalNAc and UDPGlcNAc.
GDP-sugar donors include
GDP-Man and GDP-Fuc. CMP sugar
donors are CMP-N-acetylneuraminic acid and CMP-N-glycolylneuraminic acid (sialic acid donors).
Term
Where in the cell does the biosynthesis of sugar chains take place?
Definition
The ER and the Golgi complex
Term
Biosynthesis of lactose in mammary gland?
Definition
Requires a sugar acceptor modifier for beta-galactosyltransferase. This
modifier is α-lactalbumin, which is
produced in the mammary gland. In the
presence of α-lactalbumin, the acceptor for β-galactosyltransferase is glucose and the product is lactose
Term
Biosynthesis of lactose in mammary gland: in the absence of alpha-lactalbumin.
Definition
the normal acceptor for β-galactosyltransferase is N-acetylglucosamine and the product is N-acetyllactosamine.
Term
Glycosidases and example
Definition
Cleaves sugar chains / lactose is
cleaved by beta-galactosidase or lactase to produce galactose and
glucose
Term
Glycoproteins
Definition
Glycosylated proteins
Term
What is the most common O-glycosidic linkage?
Definition
The alpha-glycosidic linkage between N-acetylgalactosamine and SER and THR on a peptide chian
Term
An N-linked sugar chain is linked to a polypeptide chain... how?
Definition
through the
β-N-glycosidic linkage between Nacetylglucosamine
and Asn on a polypeptide chain
Term
N-Glycans can be divided into “high mannose type” and “complex type.” Describe the difference...
Definition
High mannose type N-glycans contain
only N-acetylglucosamine and mannose. Complex type N-glycans contain Gal and sialic acid in addition to Nacetylglucosamine and mannose.
Term
High mannose type (or neutral type) sugar chain
Definition
contains two Nacetylglucosamine
attached to an Asn followed by a
beta-linked mannose (in red) and several alpha-linked
mannose residues at peripheral positions of the sugar chain.
Term
A complex type (or acidic type)
sugar chain
Definition
contains N-acetylglucosamine, galactose,
and sialic acid at the peripheral position of the sugar
chain.
Term
What do mannose type and complex sugar chains have in common?
Definition
There structural root and the Asn is always next to the consensus sequence, X-Serine or Threonine
Term
Major Steps in the Biosynthesis of N-Glycans
Definition
Step 1 for the biosynthesis of N-glycans involves the assembly of a high mannose type sugar chain on the lipid carrier Dolichol phosphate. The next step is the transfer of the high mannose type sugar chain from Dolichol phosphate to an Asn residue of a nascent peptide chain. Step 3 involves the processing of the high mannose type sugar chain into a complex type sugar chain.
Term
Dolichol phosphate
Definition
The high mannose type sugar chain "carrier" / Transfers chain to Asn of a nascent peptide chain / The lipid carrier dolichol phosphate is embedded
in the ER. The first step involves the stepwise assembly of a neutral type or high mannose type sugar chain on this lipid carrier. The addition of 3 glucose residues to the sugar chain signifies the completion of the assembly.
Term
Congenital Disorders of Glycosylation (CDG)
Definition
Congenital Disorders of Glycosylation are a group of disorders of abnormal synthesis of N-glycans caused by
deficiency in over 20 different enzymes associated with the synthesis of N-glycans.
Term
Aggrecan
Definition
Condroitin sulfate / Each aggrecan monomer contain a core protein to which around chondroitin sulfate and 30-50 keratan sulfate GAG chains are attached / Each GAG is covalently linked to the core protein through a Serine-Xylose-Galactose-Galactose sequence.
Term
Aggrecans and hyaluronic acid
Definition
Form aggregate
Term
Hyaluronic acid
Definition
Glucuronic acid (GlcA) and N-Acetylgucosamine (GlcNAc) joined by Beta 1-3- linkage and a Beta 1-4 for the next disaccaride / Vitreous humor of the eye, synovial fluid of joints and loose connective tissue / The only GAG that does not link to a core protein
Term
Chondriotin-4-sulfate
Definition
GlcA and N-Acetylgalactosamine and Carbon 4 is sulfated / Acidic - amino link: beta 1-3 / in cartilage, tendons, and ligaments
Term
Chondriotin-6-sulfate
Definition
GlcA and N-Acetylgalactosamine and Carbon 6 is sulfated / Acidic - amino link: beta 1-3 / in cartilage, tendons, and ligaments
Term
Dermatan Sulfate
Definition
L-Iduronic acid and N-Acetylgalactosamine and Carbon 6 is sulfated / Acidic - amino link: ALPHA 1-3 / in cartilage, tendons, and ligaments
Term
Keratan Sulfate
Definition
Composed of Galactose and GlcNAc joined by BETA-1,4- link / Then GluNAc is linked to the next Gal through a BETA 1,3 link / Disaccharide is called N-Acetyllactosamine / Carbon 6 often sulfated / Found in cartilage and cornea
Term
Heparin and Heparan Sulfate
Definition
Composed of either L-iduronic acid (L-IdoA) or D-GluA AND D-glucosamine (D-GlcN)via 2 ALPHA-1,4 link or 1 ALPHA and 1 BETA (if D-GluA) / HP and HS are the only GAGs that have an alpha linked GluN / Some carbons are usually sulfated or can be acetylated
Term
Mucopolysaccharidoses
Definition
Disorders caused by the abnormal catabolism of three specific GAGs (lysosomal storage diseases). (DS, HS, and KS) <== You need to recognize the differences in sugars
Term
Gram Positive vs Gram Negative
Definition
Positive = thick peptidoglycan layer / Negative = thin peptidoglycan layer
Term
Chemical nature of peptidoglycan
Definition
Contain GlcNAc and N-acetylmuramic acid (MurNAc) (BETA 1,4), which is GlcNAc conjugated with lactic acid in an ether linkage
Term
Polysaccharide Chain of Peptidoglycan
Definition
Contain GlcNAc and N-acetylmuramic acid (MurNAc) (BETA 1,4), which is GlcNAc conjugated with lactic acid in an ether linkage / A tetrapeptide side chain (D-glutamate, L-lysine w/ 5 glycine residues, and D-alanine) is attached to the lactic acid MurNAc /
Term
Formation of the Bacterial Peptidoglycan Cell Wall
Definition
Pentaglycine or one strand and the D-alanine on the neighboring strand (cross link) / Catalyzed by transpeptidase / BETA lactum inhibits transpeptidase cross linking
Term
How are MPSs transmitted
Definition
All are autosomal recessive except MPS II
Term
Four most well known MPS
Definition
MPS1 = Hurler (Last on DS and HS), MPS II = Hunter (Last on DS and HS), MPS III = Sanfilippo (2nd on HS), MPS IV = Morquio (Last on KS)
Term
Enzyme responsible for deficiency in MPS II (Hunter)
Definition
Iduronate sulfastase (removes sulfate)
Term
Enzyme responsible for deficiency in MPS I (Hurler)
Definition
ALPHA-L-Iduronidases (cleaves iduronic acid)
Term
Enzyme responsible for deficiency in MPS III (Sanfilippo)
Definition
Heparan N-sulfatase, Acetyl-CoA acetyl transferase, and ALPHA-N-acetyl-glucosaminidase
Term
Enzyme responsible for deficiency in MPS IV (Morquio)
Definition
Galactose 6-sulfatase or BETA Galactosidase
Term
What is the main structural difference
between this GAG and other GAGs?
Definition
Among various GAGs only heparin and
heparan sulfate contain alpha-linked
glucosamine. It should be noted that
heparin and heparan sulfate are
structurally related.
Term
What, my dear man, is a GSL?
Definition
information-rich glycoconjugates that occur in nature, mainly as constituents of biological membranes. Each GSL contains a hydrophilic sugar chain linked to a hydrophobic ceramide. The ceramide anchors the molecule into the membrane.
Term
Ceramides
Definition
Comprised of a fatty acid, which is acylated to a sphingosine backbone / can act as signaling molecules to
regulate differentiation,
proliferation, and apoptosis / Water permeability barrier
Term
The two GSLs that contain only one sugar residue...
Definition
galactosylceramide and glucosylceramide (both shown in
red). Between these two, galactosylceramide is the major GSL
of the CNS, while glucosylceramide is mainly found in visceral organs.
Term
Lactosylceramide
Definition
Formed by adding a galactose to glucosylceramide through a β-1, 4 linkage (
Term
Gb3
Definition
Formed by adding a galactose to the terminal galactose of lactosylceramide through an α-1, 4 linkage
Term
Gb4
Definition
Formed by adding an GalNAc to the terminal galactose of Gb3 through a β-1, 3 linkage
Term
Catabolism of Gb4 and the disease association
Definition
The catabolism of Gb4 yields Gb3, and the terminal β-linked GalNAc is removed (hydrolyzed, Figure 5). The enzymes that catalyze this reaction are β-hexosaminidase A and B.
This step is blocked in a total β-hexosaminidase deficiency, or type O Tay-Sachs disease, leading to the accumulation of Gb4 in the lysosome.
Term
BETA-Hexosaminidase: (Hex) A and Hex B
Definition
Hex A and Hex B
can cleave both BETA-linked GluNAc and BETA-linked GalNAc
structures. Hex A is a heterodimer consisting of 1 α and 1 BETA
subunit. Hex B consists of 2 BETA subunits.
Term
Catabolism of Gb3 and disease association
Definition
In the catabolism of Gb3, the α-linked terminal galactose in Gb3 is hydrolyzed by alpha-galactosidase
A to release galactose and lactosylceramide. A mutation in the gene that encodes α-galactosidase A
causes the impaired degradation of Gb3. The inability to catalyze this step, and the accumulation of Gb3 in
the lysosome causes Fabry disease.
Term
α-galactosidase A
Definition
Active enzyme in Gb3 catabolism / Can remove galactose from Gb3 and then if still active lactosylceramide
Term
Catabolism of GlcCer (Glucosylceramide) and associated disease
Definition
Glucosylceramide (or glucocerebroside) is hydrolyzed by
glucocerebrosidase (or β-glucosidase) to produce glucose and
ceramide. The inability to catalyze this reaction, and
the accumulation of Glucosylceramide in the lysosome causes
Gaucher disease.
Term
Catabolism of GalCer (Galactosylceramide) and associated disease
Definition
Galactosylceramide (or Galactocerebroside) is hydrolyzed
by Galactocerebrosidase (GALC or β-galactosidase) to
produce galactose and ceramide. The inability to catalyze this reaction, and the accumulation of Galactosylceramide in the lysosome causes Krabbe disease.
Term
Gangliosides
Definition
All contain sialic acid N-Acetylnueraminic Acid (NeuAc): GM3, GM2, and GM1
Term
GM3
Definition
Shortest chain / N-acetylneuraminic acid is attached to the terminal Galactose of the neutral GSL, lactosylceramide / GM3 is the major ganglioside found in visceral organs.
Term
GM2
Definition
Formed by attaching an
GalNAc to the galactose of GM3 through a β- 1,4 linkage. The inability to degrade GM2 in the lysosome causes Tay-Sachs disease.
Term
GM1
Definition
GM1 is formed by attaching Galactose to the terminal GalNAc of GM2 through a β-1,3 linkage. GM1 is the major ganglioside of the CNS and GM1 is a receptor for cholera toxin.
Term
“G” Nomenclature of Gangliosides
Definition
The nomenclature for gangliosides was created by Lars Svennerholm (Figure 12). G means ganglioside and M means the number of sialic acids. In GM1, there is only one sialic acid (NeuAc), so the ganglioside is monosialosyl. The number 1 is derived from 5-n, where n is the number of sugar residues in the main sugar chain. In GM1 there are 4 sugar residues in the main chain. Therefore, - 4 = 1.
Term
Catabolism of GM1 and associative disease
Definition
In the catabolism of GM1, the terminal galactose (in red) is hydrolyzed by β-galactosidase, releasing Galactose and GM2 (Figure 13). The inability to catalyze this reaction (due to a deficiency of β-galactosidase), and the accumulation of GM1 in the lysosome causes gangliosidosis (or generalized gangliosidosis).
Term
Catabolism of GM2 and associative disease
Definition
In the catabolism of GM2, the enzyme β-Hexosaminidase A and in the presence of a protein co-factor referred to as GM2-activator, the terminal GalNAc is hydrolyzed. This releases GalNAc and GM3. The inability to catalyze this reaction, and the accumulation of GM2 in the
lysosome causes Tay-Sachs disease. We will elaborate the enzymatic deficiencies that can cause variants of Tay-Sachs disease in the discussion session.
Term
Catabolism of GM3 and associative disease
Definition
In the catabolism of GM3, the enzyme Sialidase (or Neuraminidase)
catalyzes the hydrolysis of NeuAc, generating NeuAc and Lactosylceramide. Lactosylceramide is then subsequently converted to Glucosylceramide by β-galactosidase.
Term
Blood Group H-Antigen
Definition
Historically the "O-group": This sugar
chain contains an L-fucose and galactose together by an α-1, 2 linkage.
Term
Blood Group A-Antigen
Definition
If GalNAc is attached to the H-antigen, then the H-antigen is converted to the A-antigen and this trisaccharide is the blood group A determinant. It has GalNAc as the terminal sugar.
Term
Blood Group B-Antigen
Definition
If Galactose is attached to the H-antigen, then the Hantigen
is converted to the B-antigen, and this galactose-containing trisaccharide defines the blood group B determinant.
Term
What is the reason for blood group
incompatibility transfusion?
Definition
Presence of reciprocal antibodies in the serum of people whose RBCs lack the corresponding antigen(s). For example, type A individuals have anti-B antibody in their serum.
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